Orphanin FQ-Opioid InteractIons in Modulating Synaptic Plasticity 1. To further examine the effect of orphanin FQ on synaptic transmission and LTP in the dentate gyrus. The following questions will be addressed; a. Does orphanin FQ inhibit LTP in both the lateral and medial perforant path? b. Can orphanin FQ antagonize m opioid-induced facilitation of LTP in the lateral perforant path? c. Which phase of LTP, induction or maintenance, is interfered by orphanin FQ? d. Does endogenous orphanin FQ play a role in the modulation of LTP? To determine if orphanin FQ can antagonize opioid-induced disinhibition. a. Can orphanin FQ inhibit synaptic transmission and LTP in the presence of GABAA antagonists? b. Does orphanin FQ enhance GABAergic inhibitory postsynaptic currents (IPSCs) of dentate granule cells or facilitate LTP of IPSCs? c. Can orphanin FQ act on GABAergic terminals to affect monosynaptic IPSCs of granule cells? d. Can orphanin FQ antagonize opioid-induced hyperpolarization at the soma of dentate GABAergic interneurons. e. Is ORL-1 immunoreactivity expressed by dentate GABAergic interneurons? If they are, does the location of ORL-1 immunoreactivity support a possible effect of orphanin FQ on the interneuron soma or their axon terminals? 3. To examine it orphanin FQ inhibits NMDA channel currents in dentate granule cells. a. Does orphanin FQ depress NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) evoked in dentate granule cells? b. Does orphanin FQ depress membrane currents induced by locally applied NMDA? 4. To examine if orphanin FQ reduces presynaptic glutamate release. a. Can orphanin FQ inhibit kainate/AMPA receptor mediated EPSCs without changing granule cell responses to locally applied kainate. b. Does orphanin FQ reduce the frequency of spontaneous miniature EPSCs in granule cells. c. Can orphanin FQ reduce K+-induced, Ca2+ -dependent glutamate from hippocampal slices.